1. Field of the Invention
This invention relates to a group of synthetic esters of cephalotaxine and the use of these esters as chemotherapeutic agents for the remission of leukemia of the strain P388 in animals.
2. Description of the Prior Art
Among the alkaloids which have been isolated from Cephalotaxus harringtonia plant material are cephalotaxine and a number of its esters [Powell et al., Tetrahedron Lett. 4081 (1969); Powelll et al., Tetrahedron Lett. 815 (1970); Mikolajczak et al., Tetrahedron 28: 1995 (1972); U.S. Pat. No. 3,793,454; and U.S. Pat. No. 3,870,727]. Though cephalotaxine itself is inactive, some of its esters which are derived from relatively complex dicarboxylic acid moieties have been found to exhibit significant activity aginst experimental leukemia systems [Powell et al., J. Pharm. Sci. 61(8): 1227-1230 (August 1972)]. Two of the esters, harringtonine and homoharringtonine, have been approved for preclinical evaluation at the National Cancer Institute. However, plant material from which to extract the active esters is in critically short supply.
Cephalotaxine has been synthesized [Weinreb et al., J. Am. Chem. Soc. 97: 2503 (1975); Semmelhack et al., J. Am. Chem. Soc. 97: 2507 (1975); and Weinreb and Semmelhack, Acc. Chem. Res. 8: 158 (1975)] thereby stimulating efforts to convert it to some of its active, naturally occurring esters by reaction with appropriate acid compounds. However, very unfavorable steric (and perhaps electronic) intereactions at the reaction sites of both the cephalotaxine and the acyl moiety preclude direct esterification [Mikolajczak et al., J. Pharm. Sci. 63: 1280 (1974)]. By means of complicated and indirect routes, cephalotaxine has been converted to the active esters, deoxyharringtonine [U.S. Pat. No. 3,959,312; Mikolajczak et al., Tetrahedron Lett. 283 (1974); and Li et al., Hua Hsueh Hsueh Pao 33: 75 (1975)]; and harringtonine [Anonymous, K'o Hsueh T'ung Pao 20: 437 (1975); Chem. Abstr. 84: 105859Z (1976)].